Cellular ATP levels alone do not reliably reflect overall mitochondrial bioenergetics or mitochondrial dysfunction in Barth syndrome

Abstract

This review critically examines the question posed by Brault JF, Simon J, and Conway SJ in Journal of Translational Genetics and Genomics earlier this year: “What can ATP content tell us about Barth syndrome muscle phenotypes?”. It also offers an alternative perspective on the topic. Our answer is straightforward but warrants a detailed explanation. In the early stages of Barth syndrome, measuring adenosine triphosphate (ATP) content alone is insufficient to accurately characterize the bioenergetic profile of cells or tissues. Nevertheless, such measurements continue to attract interest - even from researchers equipped with advanced techniques - including adenosine diphosphate (ADP) and ATP assays, adenosine monophosphate (AMP) quantification, and assessments of nicotinamide adenine dinucleotide phosphate (NADPH) and nicotinamide Adenine dinucleotide (NADH) [i.e., nicotinamide adenine dinucleotide phosphate oxidized (NADP⁺) or nicotinamide adenine dinucleotide oxidized (NAD⁺)]. Assessing the rate of ATP production is a more informative and complementary approach, offering greater insight than ATP measurements alone. However, adopting a bioenergetic framework for studying Barth syndrome remains challenging. This difficulty arises largely from the profound structural and functional changes occurring within the mitochondrial compartment, which affect not only transmembrane ion transport but also the import and maturation of cytoplasmic precursors of mitochondrial proteins. Future research on Barth syndrome (BTHS) is expected to shift focus toward the central role of immature cardiolipin and monolysocardiolipin in mitochondrial membranes and their complex interactions, rather than concentrating solely on disruptions in cellular bioenergetics.

Keywords

ATP determination / Barth syndrome / bioenergetics / cardiolipin / mitochondria / monolysocardiolipin

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